Controlled activation ingestible identifier

ABSTRACT

Controlled activation identifiers for use in ingestible compositions, such as pharma-informatics enabled compositions, are provided. The identifiers include a controlled activation element that provides for activation of the identifier in response to the presence of a predetermined stimulus at a target site of interest. The invention finds use in a variety of different applications, including but not limited to, monitoring of therapeutic regimen compliance, tracking the history of pharmaceutical agents, etc.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/447,172, filed on Apr. 24, 2009, now U.S. Pat. No. 8,945,005, whichis a U.S. national stage application of International Application No.PCT/US2007/082563, filed on Oct. 25, 2007, which pursuant to 35 U.S.C. §119 (e), claims priority to the filing date of: U.S. Provisional PatentApplication Ser. No. 60/862,925 filed Oct. 25, 2006 the disclosures ofeach application are herein incorporated by reference.

INTRODUCTION

Prescription medications are effective remedies for many patients whentaken properly, e.g., according to instructions. However, studies haveshown that, on average, about 50% of patients do not comply withprescribed medication regimens. A low rate of compliance with medicationregimens results in a large number of hospitalizations and admissions tonursing homes every year. In the United States alone, it has recentlybeen estimated that the cost to the resulting from patientnon-compliance is reaching $100 billion annually.

Consequently, various methods and apparatus have been made available toimprove patient compliance with prescribed regimens in efforts toimprove patient health. To date, many different types of “smart”packaging devices have been developed. In some cases, such devicesautomatically dispense the appropriate pill. In other cases, there areelectronic controls that detect and record when the pill is taken out ofthe box.

While devices and protocols have been developed for improving patientcompliance, there is continued interest in the development of new waysof monitoring patient compliance. It would be an important advancementin clinical medicine if the actual administration and ingestion of apharmaceutical, such as a pill being dissolved in the stomach, could bemonitored in an automatic and accurate manner without dependence onpatient or medical staff reporting, where the signal generated by theidentifier in the composition is produced upon contact of thecomposition with a target location.

One system that meets the above needs is the pharma-informatics systemdescribed in PCT application serial no. PCT/US2006/016370 filed on Apr.28, 2006 and published as WO 2006/116718, the disclosure of which isherein incorporated by reference. While the system described in thisapplication provides for many benefits, reliability of signal generationcan be an issue under certain situations. For example, depending on howthe pharmaceutical composition is ingested, the particular contents ofthe stomach can have a significant impact on how the identifier in thecomposition activates. For example, signal generation can be affected bythe liquid with which a composition is ingested, e.g., water, juice,etc.

As such, of interest would be the development of an improvedpharma-informatics system in which the activation of the identifier washighly controlled, such that the signal generated by the identifierwould be independent of the particularly environment, e.g., stomachcontents, the target site where activation is desired. The presentinvention provides, for the first time, such a capability.

SUMMARY

The present invention provides for the controlled activation ofingestible identifiers, e.g., as may be incorporated intopharma-informatics enabled pharmaceutical compositions, as may bepresent in ingestible event markers, etc. Embodiments of the controlledactivation identifiers of the invention provide for robust and reliableuse despite the presence of variable conditions in the applications inwhich they are employed, e.g., inadequate degradation of apharmaceutical carrier, variations in the environment of the target siteof interest, etc.

The controlled activation identifiers of the invention are identifiersthat are activated upon association with a target site of a body. Thecontrolled activation identifier is one that is activated by thepresence of a predetermined specific stimulus at the target site, e.g.,liquid (wetting), time, pH, ionic strength, conductivity, presence ofbiological molecules (e.g., specific proteins or enzymes that arepresent in the stomach, small intestine, colon), blood, temperature,specific auxiliary agents (foods ingredients such as fat, salt, orsugar, or other pharmaceuticals whose co-presence is clinicallyrelevant), bacteria in the stomach, pressure, light, etc. Thepredetermined specific stimulus is a known stimulus for which thecontrolled activation identifier is designed or configured to respond byactivation. In certain embodiments, the signal generated by theidentifier is independent of the environment of the target site, e.g.,the nature of the fluid at the target site.

The controlled activation identifier includes a controlled activationelement that may include one or more components, where the one or morecomponents provide for the desired controlled activation in response tothe presence of the predetermined specific stimulus at the target site.In certain embodiments, the controlled activation identifier includes adried conductive medium precursor composition (e.g., a dried saltcomposition) as the controlled activation element, where this element,upon contact with a fluid (such as stomach fluid), produces a conductivemedium resulting in activation of the power source and production of anidentifying signal. The presence of the dried conductive mediumprecursor in the power source provides for a number of advantages,including the ability to obtain reliable activation of the identifierdespite variations in the environment of the target site (e.g.,variations in terms of stomach content composition), where activation ofthe identifier is desired. In yet other embodiments, the controlledactivation identifier includes a barrier as the controlled activationelement, e.g., in the form of a protective film, that is configured toprovide for activation of the identifier upon association with thetarget site of interest. Other types of controlled activation elementsinclude two or more components, such as a dried conductive medium and abarrier, e.g., as described in more detail below.

The broadcasted signal from the identifier may be received by anotherdevice, e.g., a receiver, either inside or near the body, which may thenrecord that the identifier, e.g., one that is associated with one ormore active agents and pharmaceutical composition, has in fact reachedthe target site.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows diagrammatically the effects of the pill ingestion wheresome of the pill has eroded away.

FIG. 2 provides a similar arrangement to FIG. 1, with a coil rather thantwo electrodes as the output.

FIGS. 3 to 8 provide different views of controlled activation batteriesin accordance with different embodiments of the invention.

FIG. 9 provides detail of certain implementations of an electroniccircuit of various embodiments of the invention.

FIG. 10 provides a diagrammatic, exemplary representation of the pillembodiment as part of system, in accordance with the present invention.

FIG. 11 provides two views of an open faced table format according to anembodiment of the invention.

FIG. 12 provides a schematic of an identifier encased in a disruptablecontrolled activation element according to an embodiment of theinvention.

FIG. 13 shows one exemplary design of the driver circuit that uses splitbattery electrodes for transmission, in accordance with one embodimentof the present invention.

DETAILED DESCRIPTION

The controlled activation identifiers of the invention are identifiersthat may be activated upon contact with the target site in response to aspecific predetermined stimulus. In certain embodiments, controlledactivation is provided despite wide variations in the compositionalmakeup of the target site. As such, the controlled activation identifierprovides for reliable and robust data concerning contact of thecomposition with the target site in the body, where the provided data issubstantially, if not completely, independent of any variations in theenvironment of the target site. Accordingly, despite wide variations inthe composition make up of the target site, e.g., stomach, that may beencountered in using the subject identifiers, the identifiers providefor consistent and reliable signals that are not affected by thecomposition of the target site environment. The applications of this newinformation device and system are multi-fold and described in furtherdetail in PCT application Serial No. US2006/016370 titled“Pharma-Informatics System,” and published as WO 2006/116718, and U.S.Provisional application Ser. No. 60/949,223 and titled “Ingestible EventMarker”; the disclosure of which applications described therein areincorporated by reference, as well as in the applications reviewedbelow.

In further describing the invention in greater detail, embodiments ofthe compositions are reviewed first, followed by a discussion of systemsincluding the subject compositions, methods of using the subjectcompositions and systems and various illustrative applications in whichthe compositions and methods find use. Also reviewed in greater detailbelow are kits that include the subject compositions.

Compostions

Embodiments of the invention include a controlled activation identifier,where the identifier may be associated with a carrier composition, e.g.,a pharmaceutically acceptable vehicle, and may or may not be associatedwith one or more pharmaceutical active agents. In certain embodiments,the compositions are disrupted upon administration to a subject. Assuch, in certain embodiments, the compositions are physically broken,e.g., dissolved, degraded, eroded, etc., following delivery to a body,e.g., via ingestion, etc. The compositions of these embodiments aredistinguished from devices that are configured to be ingested andsurvive transit through the gastrointestinal tract substantially, if notcompletely, intact.

As summarized above, the compositions include a controlled activationidentifier and an active agent/carrier component. Each of thesedifferent components are reviewed separately in greater detail below.

Controlled Activation Identifiers

As summarized above, the compositions of the invention includecontrolled activation identifiers. The controlled activation identifiersof the present compositions may vary depending on the particularembodiment and intended application of the composition so long as theyare activated (i.e., turned on) upon association with or contact with atarget physiological location, e.g., stomach, small intestine, largeintestine, etc. In certain embodiments, activation occurs in a mannerthat is substantially, if not completely, environment independent, butfor the presence of the predetermined activating stimulus (e.g., fluid,chemical agent, light) that is present at the target site of interest.As such, the identifier may be an identifier that emits a signal when itcontacts a target body (i.e., physiological) site, where the nature ofthe signal is not substantially affected, if affected at all, by theparticular makeup of the environment of the target site, apart from thepresence of the actual activating stimulus. For example, if the targetsite is the stomach, the activation of the identifier will besubstantially if not completely the same under a variety of differentstomach content conditions, e.g., pH variations ranging from about 1 toabout 8, etc., where apart from the presence of the fluid stimulus (theactivator being activated by wetting) the pH of the fluid does notimpact how the identifier is activated. As such, the identifiers are, incertain embodiments, characterized by emitting the same signal in termsof timing and strength following contact with a variety of differentfluid compositions having a variety of different pH values. In additionor alternatively, the identifier may be an identifier that emits asignal when interrogated after it has been activated, where activationstill occurs in a controlled manner that is independent of target siteenvironment, as reviewed above.

Depending on the needs of a particular application, the signal obtainedfrom the identifier may be a generic signal, e.g., a signal that merelyidentifies that the composition has contacted the target site, or aunique signal, e.g., a signal which in some way uniquely identifies thata particular composition from a group or plurality of differentcompositions in a batch has contacted a target physiological site. Assuch, the identifier may be one that, when employed in a batch of unitdosages, e.g., a batch of tablets, emits a signal which cannot bedistinguished from the signal emitted by the identifier of any otherunit dosage member of the batch. In yet other embodiments, theidentifier emits a signal that uniquely identifies a given unit dosage,even from other identical unit dosages in a given batch. Accordingly, incertain embodiments the identifier emits a unique signal thatdistinguishes a given type of unit dosage from other types of unitdosages, e.g., a given medication from other types of medications. Incertain embodiments, the identifier emits a unique signal thatdistinguishes a given unit dosage from other unit dosages of a definedpopulation of unit dosages, e.g., a prescription, a batch or a lifetimeproduction run of dosage formulations. In certain embodiments, theidentifier emits a signal that is unique, i.e., distinguishable, from asignal emitted by any other dosage formulation ever produced, where sucha signal may be viewed as a universally unique signal (e.g., analogousto a human fingerprint which is distinct from any other fingerprint ofany other individual and therefore uniquely identifies an individual ona universal level). In one embodiment, the signal may either directlyconvey information about the composition, or provide an identifyingcode, which may be used to retrieve information about the compositionfrom a database, i.e., a database linking identifying codes withcompositions.

The identifier may be any component or device that is capable ofproviding a detectable signal following controlled activation, e.g.,upon contact with the target site. In certain embodiments, theidentifier emits a signal once the composition comes into contact with aphysiological target site, e.g., as summarized above. For example, apatient may ingest a pill that, upon contact with the stomach fluids,generates a detectable signal.

Depending on the embodiment, the target physiological site or locationmay vary, where representative target physiological sites of interestinclude, but are not limited to: a location in the gastrointestinaltract (such as the mouth, esophagus, stomach, small intestine, largeintestine, etc.); another location inside the body, such as a parentallocation, vascular location, etc.; or a topical location; etc. Incertain embodiments, the identifier is configured to be activated uponcontact with fluid in the target site, regardless of the particularcomposition of the target site.

In certain embodiments, the identifier is dimensioned to be orallyingestible, e.g., either by itself or upon combination with aphysiologically acceptable carrier component of the composition so as toproduce a composition that can be readily administered to a subject inneed thereof. As such, in certain embodiments, the identifier element isdimensioned to have a width ranging from about 0.05 to about 2 or moremm, e.g., from about 0.05 mm to about 1 mm, such as from about 0.1 mm toabout 0.2 mm: a length ranging from about 0.05 to about 2 or more mm,e.g., from about 0.05 mm to about 1 mm, such as from about 0.1 mm toabout 0.2 mm and a height ranging from about 0.05 to about 2 or more mm,e.g., from about 0.1 mm to about 1 mm, such as from about 0.05 mm toabout 0.3 mm, including from about 0.1 mm to about 0.2 mm. In certainembodiments the identifier is 1 mm³ or smaller, such as 0.1 mm³ orsmaller, including 0.2 mm³ or smaller. The identifier element may take avariety of different configurations, such as but not limited to: a chipconfiguration, a cylinder configuration, a spherical configuration, adisc configuration, etc, where a particular configuration may beselected based on intended application, method of manufacture, etc.

The identifier may generate a variety of different types of signals,including but not limited to: RF signals, magnetic signals, conductive(near field) signals, acoustic signals, etc. Of interest in certainembodiments are the specific signals described in PCT application serialno. PCT/US2006/16370 titled “Pharma-Informatics System” and filed onApr. 28, 2006 and published as WO 2006/116718; the disclosures ofvarious types of signals in these applications being specificallyincorporated herein by reference.

The transmission time of the identifier may vary, where in certainembodiments the transmission time may range from about 0.1 μsec to about48 hours or longer, e.g., from about 0.1 μsec to about 24 hours orlonger, such as from about 0.1 μsec to about 4 hours or longer, such asfrom about 1 sec to about 4 hours. Depending on the given embodiment,the identifier may transmit a signal once or transmit a signal two ormore times, such that the signal may be viewed as a redundant signal.

In certain embodiments, the identifier may be one that is programmablefollowing manufacture, in the sense that the signal generated by theidentifier may be determined after the identifier is produced, where theidentifier may be field programmable, mass programmable, fuseprogrammable, and even reprogrammable. Such embodiments are of interestwhere uncoded identifiers are first produced and following incorporationinto a composition are then coded to emit an identifying signal for thatcomposition. Any convenient programming technology may be employed. Incertain embodiments, the programming technology employed is RFIDtechnology. RFID smart tag technology of interest that may be employedin the subject identifiers includes, but is not limited to: thatdescribed in U.S. Pat. Nos. 7,035,877; 7,035,818; 7,032,822; 7,031,946,as well as published application no. 20050131281, and the like, thedisclosures of which are herein incorporated by reference. With RFID orother smart tag technology, a manufacturer/vendor may associate a uniqueID code with a given identifier, even after the identifier has beenincorporated into the composition. In certain embodiments, eachindividual or entity involved in the handling of the composition priorto use may introduce information into the identifier, e.g., in the formof programming with respect to the signal emitted by the identifier,e.g., as described in U.S. Pat. No. 7,031,946 the disclosure of which isherein incorporated by reference.

The identifier of certain embodiments includes a memory element, wherethe memory element may vary with respect to its capacity. In certainembodiments, the memory element has a capacity ranging from about 1 bitto 1 gigabyte or more, such as 1 bit to 1 megabyte, including from about1 bit to about 128 bit. The particular capacity employed may varydepending on the application, e.g., whether the signal is a genericsignal or coded signal, and where the signal may or may not be annotatedwith some additional information, e.g., name of active agent, etc.

Controlled activation identifier components of embodiments of theinvention have: (a) a controlled activation element made up of one ormore components: and (b) a signal generation component, where the signalgeneration component is activated by the controlled activation componentto produce an identifying signal, e.g., as described above.

Controlled Activation Component

The controlled activation component is a component that activates thesignal generation element of the identifier to provide a signal, e.g.,by emission or upon interrogation, following contact of the compositionwith a target physiological site of interest, such as the stomach. Thecontrolled activation component is configured to be activated in amanner that is substantially, if not completely, independent of theparticularly compositional makeup of the target site, such thatactivation is independent of the compositional makeup of the targetsite.

As reviewed in PCT application serial no. PCT/US2006/16370 titled“Pharma-Informatics System” and filed on Apr. 28, 2006 and published asWO 2006/116718, activation of the identifier may be achieved in a numberof different ways, where such approaches include, but are not limitedto: battery completion, battery connection, etc. The differentactivation approaches disclosed in this co-pending application may bereadily adapted to provide controlled activation, as described herein,and as such are herein incorporated by reference in their entirety.

For example, controlled activation elements based on battery completionformats may employ a battery that includes, when completed, a cathode,an anode, and an electrolyte. When the composition is administered,e.g., ingested, and travels through the esophagus, it proceeds to enterthe stomach. The cathode and anode provided within the composition donot constitute a full battery. However, as the composition dissolves toexpose the cathode and anode, the stomach fluid (either by itself orwhen combined with a dried conductive precursor medium component of theidentifier) acts as the electrolyte component of the battery. The addedcomponent of the stomach fluid thus completes the battery. Therefore, asthe composition contacts the target site, e.g., by entering the stomachand dissolving to the point of cathode and anode exposure, a powersource is provided which activates the identifier, e.g., in chipconfiguration. The data signal is then transmitted.

In certain embodiments, the battery that is employed is one thatcomprises two dissimilar electrochemical materials which constitute thetwo electrodes (e.g., anode and cathode) of the battery. When theelectrode materials are exposed and come in contact with the body fluid,such as stomach acid or other types of fluid (either alone or incombination with a dried conductive medium precursor, as reviewedbelow), a potential difference, that is, a voltage, is generated betweenthe electrodes as a result of the respective oxidation and reductionreactions incurred to the two electrode materials. A voltaic cell, orbattery, can thereby be produced. Accordingly, in embodiments of theinvention, such batteries are configured such that when the twodissimilar materials are exposed to the target site, e.g., the stomach,the digestive tract, etc., during the physical and chemical erosion ofthe composition in which the signal generation element is present, avoltage is generated. The two dissimilar materials in an electrolyte areat different potentials, similar to the physics model of a ‘potatobattery’. As an example, copper and zinc when put into a cell havedifferent potentials. Similarly, gold and magnesium have differentpotentials. As a result, a potential difference between the twodissimilar materials is generated.

In certain of these embodiments, the battery power source may be viewedas a power source that exploits electrochemical reaction in an ionicsolution such as gastric fluid, blood, or other bodily fluids and sometissues. FIG. 1 provides a diagrammatic representation of the eventswhich occur when the pill is ingested and dissolved to the point thatsome of the pill has been chemically and/or physically eroded away.Electrode materials 32 and 33 are now in an ionic solution 39 (which maybe made up of target site fluid alone or target site fluid combined witha dried conductive medium precursor). This configuration creates a lowvoltage (V−) and a high voltage (V+) as applied to an electronic circuit40. The two outputs of that electronic circuit 40 are E0 41 and E1 42,which are the signal-transmission electrodes on the top surface. In analternate embodiment no shown in FIG. 2 where the signal generationelement 30 includes a single electrode, the output is E0 41.

FIG. 2 shows a similar arrangement as in FIG. 1. However, instead ofhaving two electrodes as the output, a coil is provided. Electrodematerials 32 and 33 are applied to the electronic circuit 40 of signalgeneration element 30. The outputs of the electronic circuit 40 arecoupled to a coil 43. This configuration provides that a battery iscreated by Electrode materials 32 and 33 when exposed to ionic solution.This battery drives the circuit 40, which creates an oscillatingfrequency. This oscillating current goes through the coil and generatesa RF magnetic signal. Unlike near-field quasi-static electrical signals,which may suffer from significant attenuation through body tissues, theRF magnetic signal can be transmitted through body tissues with lessattenuation. The RF magnetic signal is then picked up by an external orinternal receiver device that has a magnetic-signal detection mechanism.If a broadcast is provided at a high enough frequency, a pager-likedevice that is worn by the patient will detect whenever a pill isingested.

FIGS. 1 and 2 illustrate an identifier 30 having a signal generationelement 40 powered by electrochemical reaction. Signal generationelement 40 is electrically connected to electrode electrodes 32 and 33,which are made of two different materials and are electrically insulatedfrom each other. When electrodes 32 and 33 are immersed in an ionicsolution 39, a potential difference develops between them; for instance,electrode 33 rises to a higher potential V+ while electrode 32 falls toa lower potential V−. This potential difference can be used to powercircuitry 40.

Electrodes 32 and 33 can be implemented in various ways; for instance,areas on opposing surfaces of an integrated circuit chip can be coatedwith two different metals, and the entire chip can be placed in theionic solution. Alternatively, electrodes 32 and 33 may extend away fromelement 40 as shown. Other arrangements may also be used.

Electrodes 32 and 33 can be made of any two materials appropriate to theenvironment in which the identifier 30 will be operating. The activematerials are any pair of materials with different electrochemicalpotentials. For instance, in some embodiments where ionic solution 39comprises stomach acids, electrodes 32 and 33 may be made of a noblemetal (e.g., gold, silver, platinum, palladium or the like) so that theydo not corrode prematurely. Alternatively, the electrodes can befabricated of aluminum or any other conductive material whose survivaltime in the applicable ionic solution is long enough to allow identifier30 to perform its intended function. Suitable materials are notrestricted to metals, and in certain embodiments the paired materialsare chosen from metals and non-metals, e.g., a pair made up of a metal(such as Mg) and a salt (such as CuI). With respect to the activeelectrode materials, any pairing of substances—metals, salts, orintercalation compounds—with suitably different electrochemicalpotentials (voltage) and low interfacial resistance are suitable.

A variety of different materials may be employed as the batteryelectrodes. In certain embodiments, electrode materials are chosen toprovide for a voltage upon contact with the target physiological site,e.g., the stomach, sufficient to drive the signal generation element ofthe identifier. In certain embodiments, the voltage provided by theelectrode materials upon contact of the metals of the power source withthe target physiological site is 0.001 V or higher, including 0.01 V orhigher, such as 0.1 V or higher, e.g., 0.3 V or higher, including 0.5volts or higher, and including 1.0 volts or higher, where in certainembodiments, the voltage ranges from about 0.001 to about 10 volts, suchas from about 0.01 to about 10 V.

Materials and pairings of interest include, but are not limited to thosereported in Table 1 below.

TABLE 1 Anode Cathode Metals Magnesium, Zinc Sodium (†), Lithium (†)Iron and alloys thereof Salts Copper salts: iodide, chloride, bromide,sulfate, formate, (other anions possible) Fe³⁺ salts: e.g.orthophosphate, pyrophosphate, (other anions possible) Oxygen (††) onplatinum, gold or other catalytic surfaces Intercalation Graphite withLi, Vanadium oxide compounds K, Ca, Na, Mg Manganese oxide (†) Protectedanodes: certain high energy anode material such as Li, Na, and otheralkali metals are unstable in their pure form in the presence of wateror oxygen. These may however be used in an aqueous environment ifstabilized. One example of this stabilization is the so-called“protected lithium anode” developed by Polyplus Corporation (Berkeley,CA), where a polymer film is deposited on the surface of lithium metalto protect it from rapid oxidation and allow its use in aqueousenvironment or air ambient. (Polyplus has IP pending on this). (††)Dissolved oxygen can also serve as a cathode. In this case, thedissolved oxygen in the bodily fluids would be reduced to OH— at asuitable catalytic surface such at Pt or gold. Other catalysts are alsopossible.

In certain embodiments, one or both of the metals may be doped with anon-metal, e.g., to enhance the voltage output of the battery.Non-metals that may be used as doping agents in certain embodimentsinclude, but are not limited to: sulfur, iodine and the like.

In certain embodiments, the electrode materials are cuprous iodine (CuI)or cuprous chloride as the anode and magnesium (Mg) metal or magnesiumalloy as the cathode. Embodiments of the present invention use electrodematerials that are not harmful to the human body.

Additional battery configurations of interest include, but are notlimited to, those described in: U.S. Provisional Application Ser. No.60/889,868 titled “Pharma Informatics System Power Source,” and filed onFeb. 14, 2007; U.S. Provisional Application Ser. No. 60/889,870 titled“Pharma Informatics System Power Source Having High Surface AreaCathodes,” and filed on Feb. 14, 2007; and U.S. Provisional ApplicationSer. No. 60/889,871 titled “Pharma Informatics System Having ShortResistant Series Battery”; the disclosures of which applications areherein incorporated by reference.

The controlled activation element of the identifier that provides forcontrolled activation may be responsive to a variety of different typesof stimuli. Stimuli of interest for which the controlled activationelement can be configured to be responsive to include but are notlimited to: liquid (wetting), time, pH, ionic strength, conductivity,biological molecules (e.g. specific proteins or enzymes that are presentin the stomach, small intestine, colon), blood, temperature, specificauxiliary agents (foods ingredients such as fat, salt, or sugar, orother pharmaceuticals whose co-presence is clinically relevant),bacteria in the stomach, pressure, and light.

The controlled activation element is made up of one or more componentsthat provides for the desired controlled activation functionality, suchthat the controlled activation element is responsive to the stimulus ofinterest. The nature of the component or components that make up thecontrolled activation element may vary. For example, where the stimulusof interest is temperature, the controlled activation element may be abarrier of a material, such as a film (e.g., a polymeric film) whosesolubility is a function of temperature, specifically one that becomessoluble at or near body temperature. Such a film may beinsoluble/impermeable to water at room temperature but soluble/permeableat 37° C. Materials of interest that may be used for such films include,but are not limited to the polymeric materials listed below. In thoseembodiments where pressure is the stimuli of interest, the controlledactivation element may be a pressure sensitive material, e.g., a capsuleor shell (for example, made of a cellulosic material), that has aspecific mechanical strength such that at a pressure threshold above thethreshold the element will be crushed and allow the identifier to beactivated and transmit a signal. In other embodiments of interest, thestimulus may be light. For example, the stimulus may be a fluorescentlabel which has been attached to a tumor. As the identifier passes bythe tumor, the controlled activation element may include a componentthat provides light at a stimulating wavelength for the label and also acomponent that detects emitted light from the label. Any convenientlight source and detector may be employed. When the detector componentdetects the emitted light, it will activate the identifier in acontrolled activation manner.

In certain embodiments, the one or more controlled activation componentsof the invention provide for controlled activation, i.e., activation ina manner that is substantially, if not completely, independent of targetsite environment, as reviewed above. In one embodiment of interest, thecontrolled activation component includes a dried conductive medium that,upon combination with target site fluid, produces an ionic medium in thepresence of the first and second dissimilar materials to activate thebattery, e.g., as reviewed above. A representative configuration of suchactivation component that includes a dried conductive medium precursorcomponent is provided in FIG. 3. FIG. 3 shows battery element withelectrode materials 32 and 33 present on a surface of solid support 50.Positioned between electrode materials 32 and 33 is dried conductivemedium precursor 34.

When present, the dried conductive medium precursor may be any of avariety of different types of compositions. Compositions of interestinclude, but are not limited to: salts of physiologically acceptableelectrolytes, such as but not limited to: sodium ion, chloride ion,potassium ion and calcium ion, magnesium ion, etc. Specificphysiologically compatible salts of interest include, but are notlimited to: KCl, NaCl, MgCl₂, and the like. Aspects of the inventioninclude the presence of a dried conductive medium precursor. When theprecursor is a salt, e.g., as described above, the dried salt may beprovided in any convenient format, such as a lyophilized saltcomposition.

A variation of the embodiment shown in FIG. 3 is depicted in FIG. 4. InFIG. 4, the identifier includes a protective barrier, where theprotective barrier serves to retain dried conductive medium precursor.The protective barrier 35 may have a variety of different configurationsand functions, in addition to serving to retain the precursor with theidentifier. For example, the protective barrier 35 may serve to providefor controlled metering of target site liquid to the dried conductivemedium precursor 34. In FIG. 4, ion permeable membrane 35 is providedwhich controls which portion of the target site fluid combines with thedried conductive medium precursor 34 to activate the battery. Anyconvenient semi-permeable membrane may be employed. The semi-permeablemembrane may comprise ePTFE, Dacron®, polyurethane, silicone rubber,poly(lactide-co-glycolide) (PLGA), poly(caprolactone) (PCL),poly(ethylene glycol) (PEG), collagen, polypropylene, cellulose acetate,poly(vinylidene fluoride) (PVDF), naflon or other biocompatiblematerial. The pore size of the membrane may vary depending on theparticular configuration, where in certain embodiments the membrane havea pore size (MW cutoff of about 1000 d or less, such as about 500 d orless, including about 250 d or less, e.g., about 100 d or less, such asabout 50 d or less). In certain embodiments, the membrane is a wateronly permeable membrane, such that water, but little if any other fluidconstituents at the target site, pass through the membrane to reach tothe dried conductive medium precursor of the identifier.

Instead of a semi-permeable membrane, a solid barrier that includes oneor more fluid flow paths may be present. For example, in FIG. 5, thebattery includes solid barrier 36 which includes a fluid flow path 37.While fluid flow path 37 may have any convenient dimensions, in certainembodiments fluid flow path is a capillary flow path, such that fluidflows through the flow path via capillary action. In certainembodiments, the fluid flow path has microscale cross-sectional innerdimensions such that the independent dimensions are greater than about 1μm and less than about 1000 μm. These independent cross sectionaldimensions, i.e. width, depth or diameter depending on the particularnature of the fluid flow path or channel, may range from about 1 to 200μm, such as from about 10 to 150 μm, and including from about 20 to 100μm with, the total inner cross sectional area ranging from about 100 to40,000 μm², such as from about 200 to 25,000 μm². The inner crosssectional shape of the channel may vary greatly. Configurations include,but are not limited to: rectangular, square, rhombic, triangular orV-shaped, D-shaped, U-shaped, circular, semicircular, ellipsoid and thelike. While the fluid flow path as shown in FIG. 5 is straight, the flowpath may, course, have a variety of different configurations, such thatit may include bends or turns, be curvilinear, etc., as desired. Anyconvenient fabrication techniques may be employed, where “lab on-a-chip”technologies, such as but not limited to those described in U.S. Pat.Nos. 6,939,451; 6,838,156; 6,730,206; 6,623,860; 6,613,525; 6,306,273;6,284,113; 6,176,962; 6,103,199; 6,056,860; 6,054,034; 5,935,401;5,858,188; 7,069,952; 7,033,474; 6,857,449; 6,841,193; 6,660,367;6,551,836; 6,517,234; 6,509,085; the disclosures of which are hereinincorporated by reference.

In certain embodiments, the surface of the flow path may be modified toprovide for desired fluid flow properties. For example, the surfaceenergy of one or more surfaces of the flow path may be modified toprovide for enhanced fluid flow through the capillary. For example, thesurface energy of one or more surfaces of the flow path may beincreased, such that the surface becomes more hydrophilic. A variety ofdifferent surface energy modification protocols may be employed, wherethe particular protocol chosen may depend on the particular compositionof the barrier and the desired surface energy properties. For example,if one wishes to increase the surface energy of a given surface, thesurface may be subjected to plasma treatment, contacted with a surfaceenergy modification such as surface modifying polymer solutionsdescribed in, e.g., U.S. Pat. Nos. 5,948,227 and 6,042,710, each ofwhich is incorporated herein in its entirety for all purposes.

In certain embodiments, the barrier may be one that disrupts uponcontact with a fluid having sufficient conductivity to activate theidentifier in a predetermined manner, either alone or in combinationwith dried conductive medium precursor that may be present on thesupport. For example, FIG. 6 shows an embodiment where a barrier 38 ispresent that, upon contact with a fluid meeting predetermined criteria,e.g., conductivity, pH, etc., disrupts (such as by dissolution) toexpose dried conductive medium precursor 34 to fluid and therebyactivate the battery.

While FIG. 6 shows the presence of such a barrier with a driedprecursor, the dried precursor need not be present. For example, FIG. 7shows an embodiment where a dried conductive medium precursor is notpresent. In this embodiment, protective layer 38 protects electrodes 32and 33 and substrate 50. Upon contact with a fluid meeting predeterminedcriteria, e.g., conductivity, pH, etc., protective layer 38 disrupts(such as by dissolution) to expose dried electrodes 32 and 33 to fluidand thereby activate the battery.

A variation of the embodiment shown in FIG. 7 is provided in FIG. 8. InFIG. 8 barrier 38′ is a time controlled dissolution composition, i.e., acomposition that dissolves in a time dependent manner upon contact witha fluid, where the dissolution time of a given material in the fluid ofinterest is known prior to contact with the fluid, such that thedissolution time is predetermined. In certain embodiments, thiscomposition is a polymer composition, such as a polymer compositionemployed in time controlled release pharmaceutical compositions.Polymeric compositions of interest that may be employed include, but arenot limited to: water-swellable compositions (whose thickness impartscontrolled time dissolution), such as compositions made up of a binder(such as vinyl polymers, such as polyvinylpyrrolidone, polyvinylalcohol, and the like; cellulosic polymers, such ashydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, and the like; acrylic polymers and copolymerssuch as methacrylic acid copolymers, ethyl acrylate-methylmethacrylatecopolymers, and the like; natural or synthetic gums, such as guar gum,arabic gum, xanthan gum, and the like; proteins or carbohydrates, suchas gelatin, pectin, and the like; and mixtures thereof) and a polymericcoating particle (such as particles made up of cellulosic polymers, suchas methylcellulose, carboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, and the like; vinylpolymers, such as polyvinylpyrrolidone, polyvinyl alcohol, and the like;acrylic polymers and copolymers, such as acrylic acid polymer,methacrylic acid copolymers, ethyl acrylate-methyl methacrylatecopolymers, and the like; and mixtures thereof) and described in U.S.Pat. No. 6,190,692 (the disclosure of which is herein incorporated byreference); and the like.

It is noted that with the time-delay configuration as exemplified by theembodiment of FIG. 8, it is not necessary for the barrier, e.g.,membrane, to cover both electrodes and the space in between. In certainembodiments, only one electrode is covered and subsequently activated,since the battery will not discharge unless both electrodes areactivated. As such, in certain embodiments just one electrode covered bya “patch” of material that dissolves away, resulting in activation.

The above discussion, in combination with FIGS. 1 to 8, provides detailsof certain non-limiting embodiments of the controlled activationelements of the subject identifiers. As described above, the controlledactivation element may include a single component, e.g., a barrier, adried conductive medium, etc., or be a composite controlled activationelement of two or more components that work together to providecontrolled activation functionality to the identifier (e.g., where thecontrolled activation element includes both a barrier and a driedconductive medium. In certain embodiments, the various controlledactivation mechanisms described above can be combined to achievecascaded or multi-component activation. For example, several types offilm can be deposited or otherwise present on an identifier, or afilm-based activation can be combined with a capsule-based activationand a salt-based activation. Examples of such schemes include but arenot limited to the following.

In one embodiment, several layers of film are present on the identifier,so that the first layer protects the identifier duringprocessing/storage, the second layer dissolves when a target pH isreached, and the third layer releases a salt to finally activate thedevice and transmit a signal. Advantages of this type of approachinclude additional protection and margin against accidental or prematureactivation. The device can only activate once all the activation eventshave occurred. Another use of a multilayered film is as ananti-tempering mechanism, because the identifier will activate onlyafter the specific sequence of conditions have been encountered, whichmakes it difficult or impossible to incorrectly active the device bydipping it into a single fluid or holding it in the mouth withoutswallowing.

Another example is multiple patches of activating films that aredeposited on different parts of the activating surface of theidentifier, e.g., the electrodes. For example, the battery on theidentifier may be micropatterned or covered by several micropatternedpatches of film that activate in different parts of the GI tract, sothat a signal is transmitted by an identifier once it reaches thestomach, then transmitted again when the identifier reaches theintestine, and again when it reaches the colon, etc. This configurationallows the same identifier to detect multiple events, such as passagethrough different parts of the GI tract.

Another use of combined activation is for the identifier to detect acombined event, e.g., to detect when a patient has ingested anidentifier along with a certain type of food, drink, or othermedication. This allows detection of interactions or of patientsingesting things they are not supposed to with their medication.

Another use in certain embodiments is to transmit a different signaldepending on different conditions in the GI tract. An identifier may bebuilt with two separate transmitting elements that are activated viadifferent mechanisms, so that in addition to activation of theidentifier information can be obtained about the GI tract's condition.For example, one element is activated by a low pH condition and theother, in a high pH condition.

Identifiers of the invention may be associated with carrier compositionsthat can potentially interfere with the functionality of the identifierif the carrier does not degrade properly upon ingestion. For example, atypical gel capsule (e.g., made by Capsugel, Peapack, N.J.) dissolves inaqueous solutions in a manner that is strongly dependent on physical(e.g., temperature) and chemical environment of the device. Undercertain combinations of conditions, the gel residue may only dissolvepartially, leaving an undissolved or congealed layer or residue on thesurface of an identifier associated with the capsule. Such remainingresidue can completely prevent activation of the device or reduce signalstrength. Where the identifier is configured to be associated with a gelcapsule formulation or analogous carrier structure, in certainembodiments the controlled activation element is one which is designedto ensure that when the intended activation time or chemical/physicalenvironment is reached, the device is not hindered by residue from acarrier such as a gel capsule. One configuration designed to presentremaining residue from interfering with function of the device includesa soluble film deposited on the device surface such that the partiallydissolved gel residue adheres to this film. Upon ingestion, the filmthen dissolves away in a timed or chemically-sensitive manner, leavingthe device surface free of gel. In another approach, an absorbentsubstance (e.g. powder or granular form) is added to the gel capsulesuch that the partially dissolved gel residue adheres to the powder orgranules. The powder then falls away from the device. Examples mayinclude any edible powder or granules, such as starch, sugar, salt, orproteins. In another configuration, a substance added to the gel capsulethat swells significantly upon wetting, resulting in the bursting of thegel capsules and release of the device. Examples include swellingpolymer matrices such as pharmaceutical excipients that aredisintegrating agents (the so-called superdisintengrants) anddissolution aids. Examples are Ac-Di-Sol (made by FMC) and carboxymethylcellulose and related compounds. In yet another embodiments, a substanceis added to the gel capsule that generates heat upon dissolution. Gelcapsule dissolution is very sensitive to heat. Certain salts undergoexothermic dissolution reaction in water. Such salts can be added to thecapsule or deposited on the surface of the device so that upon wetting,sufficient heat is generated to raise the local temperature by a few °C. (e.g., 0.1 to 20° C., such as 1 to 10° C., including 1 to 5° C.).Examples of these salts are: ZnC₂, BaCl₂, MgCl₂. In yet anotherembodiment (e.g., as shown in FIG. 12), a strip or sheet 120 ofpolymeric material (e.g., ethyl cellulose) with a spring-like propertyis included inside the gel capsule 122. The strip is folded or coiledand constrained at its ends by a water soluble polymer (e.g.,hydroxypropyl cellulose) 124. Present inside of the strip is identifier126. Upon wetting (indicated by arrow), the water soluble polymer 124dissolves away, allowing the strip 120 or sheet to unfold with enoughmechanical force to burst open the gel capsule 122 and release thedevice 126 clear of the capsule.

In controlled activation elements that include a film or layer, e.g., asdescribed above, the film or layer can be on only one surface of thedevice or a portion thereof (e.g., it may cover only an active surfaceof the device or electrode elements present thereon) or it may cover allsurfaces of the device, such that the device is encased or encapsulatedin the film or layer. In certain embodiments, the identifier device isencapsulated entirely in a polymeric pellet that dissolves in responseto chemical/physical environment and/or time. The resultant pellet isplaced inside a gel cap or compressed into a tablet, where it alsoprotects the identifier from damage caused by the large compressionforces used to make a tablet.

Film barriers have been described in the above discussion in terms oftheir functionality in providing controlled activation for theidentifier. In addition or alternatively to this function, a filmbarrier may be present that is configured to prevent mechanical damageto the identifier (e.g., damage to IC or battery layers) duringprocessing, handling, bottling, or storage. For example, the deviceincludes in certain embodiments a film that prevents activation ordegradation of the device performance or lifetime during processingsteps (e.g., when the battery may get wet) or storage (e.g., viamoisture absorption from the atmosphere). For example, a film that issoluble only in low pH solution is employed in certain instances toprotect the device during processing in high pH aqueous environments. Incertain embodiments, a film is present that prevents device-to-devicecontact (e.g., when multiple devices are placed in the same gel capsuleor in a bottle).

Another type of controlled activation identifier is one that isconfigured so that it is activated only upon elimination of theidentifier from the body. For example, the identifier may be covered(partially or wholly) in a barrier layer that is impervious and remainsintact while the identifier passes through the GI tract. Uponelimination of the identifier from the GI tract, the barrier maydissolve when it comes in contact with water present in a wasteelimination device, e.g., toilet. For example, the barrier may besensitive to chemicals present in the water of the toilet. When thebarrier is disrupted, the water activates the identifier to emit asignal, where the signal may be picked up by a sensor, e.g., associatedwith the toilet. To prevent tampering, a second controlled activationelement that is disrupted by the GI tract may be included, such thatactivation only occurs when this second element is disrupted by the GItract and the first barrier is disrupted by the toilet water.

The identifiers may be fabricated using any convenient processingtechnology, for example, planar processing technology, e.g., as employedin MEMS fabrication, may be employed, coupled with depositiontechnologies, such as precipitation, for providing the dried conductivemedium precursor.

The subject controlled activation batteries may be fabricated in anumber of different ways. In certain embodiments, fabrication protocolswhich may be categorized as “planar” processing protocols are employed,as developed in greater detail below.

After the battery is activated, further activation configurations can beemployed to activate the signal generation component. For example, thesignal generation component can be activated through the activation ofthe gate of a metal oxide semiconductor (MOS) circuit, such as a CMOSswitch. Activation of the gate of the MOS circuit can be based on one ormore parameters, which include but are not limited to: gate current,gate charge, and gate capacitance. The gate current, for activationpurposes, can be a function of the conductivity of surrounding bodyfluids or tissues. Such conductivity can further be a function of one ormore parameters, which include but are not limited to: solutionconcentration, solution pH value, ionic content of solution, enzymaticcontent of solution, temperature, and carrier mobility. Carrier mobilitycan also be a function of temperature. Similarly, the gate charge can bea function of one or more parameters, which include but are not limitedto: solution composition, crystal potential, electrical potential,gravitational potential, gate capacitance, and carrier concentration.The carrier concentration can also be a function of temperature. Thegate capacitance can be a function of the capacitive geometry of thegate, which can further be a function of pressure, a resonant input, orthe characteristics of a dielectric material coupled to the gate. Thecharacteristics of the dielectric material can vary with one or moreparameters, which include but are not limited to: chemical contents of adigestive tract, chemical character of a physiological location, andamount of dissolution of the dielectric material in body fluids.

Signal Generation Component

The signal generation component of the identifier element is a structurethat, upon activation by the controlled activation component, emits adetectable signal, e.g., that can be received by a receiver, e.g., asdescribed in greater detail below. The signal generation component ofcertain embodiments can be any convenient device that is capable ofproducing a detectable signal and/or modulating transduced broadcastpower, upon activation by the activation component. Detectable signalsof interest include, but are not limited to: conductive signals,acoustic signals, etc. As reviewed above, the signals emitted by thesignal generator may be generic or unique signals, where representativetypes of signals of interest include, but are not limited to: frequencyshift coded signals; amplitude modulation signals; frequency modulationsignals; etc.

In certain embodiments, the signal generation element includescircuitry, as developed in more detail below, which produces orgenerates the signal. The type of circuitry chosen may depend, at leastin part, on the driving power that is supplied by the power source ofthe identifier. For example, where the driving power is 1.2 volts orabove, standard CMOS circuitry may be employed. In other embodimentswhere the driving power ranges from about 0.7 to about 1.2 V,sub-threshold circuit designs may be employed. For driving powers ofabout 0.7 V or less, zero-threshold transistor designs may be employed.

In certain embodiments, the signal generation component includes avoltage-controlled oscillator (VCO) that can generate a digital clocksignal in response to activation by the activation component. The VCOcan be controlled by a digital circuit, which is assigned an address andwhich can control the VCO with a control voltage. This digital controlcircuit can be embedded onto a chip that includes the activationcomponent and oscillator. Using amplitude modulation or phase shiftkeying to encode the address, an identifying signal is transmitted.

The signal generation component may include a distinct transmittercomponent that serves to transmit the generated signal to a remotereceiver, which may be internal or external to the patient, as reviewedin greater detail below. The transmitter component, when present, maytake a number of different configurations, e.g., depending on the typeof signal that is generated and is to be emitted. In certainembodiments, the transmitter component is made up of one or moreelectrodes. In certain embodiments, the transmitter component is made upof one or more wires, e.g., in the form of antenna(e). In certainembodiments, the transmitter component is made up of one or more coils.As such, the signal transmitter may include a variety of differenttransmitters, e.g., electrodes, antennas (e.g., in the form of wires)coils, etc. In certain embodiments, the signal is transmitted either byone or two electrodes or by one or two wires. A two-electrodetransmitter is a dipole; a one electrode transmitter forms a monopole.In certain embodiments, the transmitter only requires one diode drop ofpower. In some embodiments, the transmitter unit uses an electric dipoleor electric monopole antenna to transmit signals.

FIG. 9 shows the detail of one implementation of an electronic circuitthat can be employed in an identifier according to the presentinvention. On the left side are the two battery electrodes comprising afirst metal (electrode 32) and a second metal (electrode 33). Thesemetals, when in contract with an electrolyte (produced upon contact withtarget site fluid, either alone or in combination with dried conductivemedium precursor, as reviewed above), form a battery that provides powerto an oscillator 61, in this case shown as a schematic. The first metal(electrode 32) provides a low voltage, (ground) to the oscillator 61.The second metal (electrode 33) provides a high voltage (V_(high)) tothe oscillator 61. As the oscillator 61 becomes operative, it generatesa clock signal 62 and an inverted clock signal 63, which are oppositesof each other. These two clock signals go into the counter 64 whichsimply counts the number of clock cycles and stores the count in anumber of registers. In the example shown here, an 8 bit counter isemployed. Thus, the output of counter 64 begins with a value of“00000000,” changes to “00000001” at the first clock cycle, andcontinues up to “11111111.” The 8-bit output of counter 64 is coupled tothe input of an address multiplexer (mux) 66. In one embodiment, mux 65contains an address interpreter, which can be hard-wired in the circuit,and generates a control voltage to control the oscillator 61. Mux 65uses the output of counter 64 to reproduce the address in a serial bitstream, which is further fed to the signal-transmission driving circuit.Mux 65 can also be used to control the duty-cycle of the signaltransmission. In one embodiment, mux 65 turns on signal transmissiononly one sixteenth of the time, using the clock counts generated bycounter 64. Such a low duty cycle conserves power and also allows otherdevices to transmit without jamming their signals. The address of agiven chip can be 8 bits, 16 bits or 32 bits. Typically, more than 8bits will be used in a product because there are so many different typesof pharmaceuticals. Each pharmaceutical will have its own specificaddress.

The present invention also allows the possibility that, whereappropriate, each pharmaceutical batch can be provided with a batchspecific address. This allows identification of where the pill was made,when the pill was made, and in what batch it was made. In some cases,each pill will have a unique identifier. This would be particularlyuseful when drugs are more likely to be subsequently stolen or usedillicitly, and thus should be tracked, or where questions ofcontamination may arise.

According to one embodiment, mux 65 produces a control voltage, whichencodes the address serially and is used to vary the output frequency ofoscillator 61. By example, when the control voltage is low, that is,when the serial address bit is at a 0, a 1 megahertz signal is generatedby the oscillator. When the control voltage is high, that is, when theaddress bit is a 1, a 2 megahertz signal is generated the oscillator.Alternately, this can be 10 megahertz and 20 megahertz, or a phase shiftkeying approach where the device is limited to modulating the phase. Thepurpose of mux 66 is to control the frequency of the oscillator or an ACalternative embodiment of the amplified signal of oscillation.

The outputs of mux 66 are coupled to electrode drive 66 which can drivethe electrodes to impose a differential potential to the solution, drivean oscillating current through a coil to generate a magnetic signal, ordrive a single electrode to push or pull charge to or from the solution.

In this manner, the device broadcasts the sequence of 0's and 1's whichconstitute the address stored in mux 65. That address would be broadcastrepeatedly, and would continue broadcasting until the first metal or thesecond metal (32 and 33) is consumed and dissolved in the solution, whenthe battery no longer operates.

In a further embodiment, the device can avoid the use of separatetransmission electrodes by using the battery electrodes fortransmission. FIG. 13 shows an example of such a configuration. Thedriver circuit 206 essentially contains a switch coupled between theanode 204 and the cathode. This switch can be turned on or off by theaddress signal from the logic circuit 201. When the switch is turned on,the battery for the driver circuit is effectively short circuited withinthe chip. Consequently, a current 207 flows through the body from thecathode to anode 204. The resistance of the body tissue can therebygenerate a voltage difference, which can be readily detected by, forexample, a differential amplifier.

Other configurations for the signal generation component are of coursepossible. Other configurations of interest include, but are not limitedto: those described in copending PCT application serial no.PCT/US2006/016370; the disclosure of which is herein incorporated byreference.

Additional Components

Depending on the particular embodiment, the identifier may include anumber of different additional components. Some components of interestinclude, but are not limited, those reviewed below.

Deactivation Component

Where desired, the identifier may also include a deactivation mechanismthat disables the identifier if the identifier is not employed asintended, e.g., the composition with which it is associated is notingested. In certain embodiments, the identifier includes a deactivationmechanism that deactivates the identifier so that it if someone tries toturn it on in a way other than ingesting it, the identifier isdeactivated and no signal can be transmitted. Deactivation mechanisms ofinterest may include one or more of the following components: inclusionof a light-sensitive film that destroys a component of the identifier,e.g., memory, upon exposure to light, a light sensitive batterymaterial, e.g., that is disrupted or destroyed if exposed to light, anidentifier that includes components which are sensitive to andinactivated in response to exposure to oxygen, air, moisture, etc.Inactivation of the identifier may include opening a trace, shorting atrace, reducing battery voltage, etc.

Power Enhancers

Where the activator is a power source that is turned on upon contactwith a target physiological site, in certain embodiments, circuits forenhancing or boosting voltage output of the power source, e.g., battery,are provided, e.g., charge pumping circuits, charge doublers, etc. Suchvoltage enhancing elements may enhance the voltage output by at about2-fold or more, such as by about 5-fold or more.

Power Storage

In certain embodiments, the activation component includes a powerstorage element. For example, a duty cycle configuration may beemployed, e.g., where slow energy production from a battery is stored ina power storage element, e.g., in a capacitor, which then provides aburst of power that is deployed to the signal generation component. Incertain embodiments, the activation component includes a timing elementwhich modulates, e.g., delays, delivery of power to the signalgeneration element, e.g., so signals from different compositions, e.g.,pills, that are administered at substantially the same time are producedat different times and are therefore distinguishable.

Additional Features

In certain embodiments, the compositions are characterized by having oneor more of the following features. In certain embodiments, thecompositions include an identifier which employs a conductive near-fieldmode of communication in which the body itself is employed as aconductive medium. In such embodiments, the compositions includecircuitry that, when freed from the composition upon disruption of thecomposition (e.g., as described above) the circuitry comes into directcontact with the body and does not remain encapsulated or protected insome manner. In these embodiments, the signal is not a magnetic signalor high frequency (RF) signal. In certain embodiments, the systems areones that include a receiver which is stably associated with the body,e.g., implanted or topically applied to an external location, such thatthe systems are distinguished from those in which an external devicethat is not stably associated with the body is employed to collect data.In certain embodiments, the compositions do not include an imagingsystem, e.g., camera or other visualization or imaging element, orcomponents thereof, e.g., CCD element, illumination element, etc. Incertain embodiments, the compositions do not include a sensing element,e.g., for sensing a physiological parameter, beyond the activator whichdetects contact with the targeted physiological site. In certainembodiments, the compositions do not include a propulsion element. Incertain embodiments, the compositions do not include a sampling element,such as a fluid retrieval element. In certain embodiments, thecompositions do not include an actuatable active agent delivery element,such as an element that retains an active agent with the compositionuntil a signal is received that causes the delivery element to releasethe active agent.

Active Agent Component

Certain embodiments of the subject compositions include an active agentcomponent. “Active agent” includes any compound or mixture of compoundswhich produces a physiological result, e.g., a beneficial or usefulresult, upon contact with a living organism, e.g., a mammal, such as ahuman. Active agents are distinguishable from such components asvehicles, carriers, diluents, lubricants, binders and other formulatingaids, and encapsulating or otherwise protective components. The activeagent may be any molecule, as well as binding portion or fragmentthereof, that is capable of modulating a biological process in a livingsubject. In certain embodiments, the active agent may be a substanceused in the diagnosis, treatment, or prevention of a disease or as acomponent of a medication. In certain embodiments, the active agent maybe a chemical substance, such as a narcotic or hallucinogen, whichaffects the central nervous system and causes changes in behavior.Active agents of interest include those listed in PCT application serialno. PCT/US2006/016370; the disclosure of which list is hereinincorporated by reference. Broad categories of active agents of interestinclude, but are not limited to: cardiovascular agents; pain-reliefagents, e.g., analgesics, anesthetics, anti-inflammatory agents, etc.;nerve-acting agents; chemotherapeutic (e.g., anti-neoplastic) agents;etc. The active agent of the compositions are typically present in apharmaceutically acceptable vehicle or carrier, e.g., as describedbelow. In certain embodiments, the active agent is present in an amountof from about 0.1% to about 90% by weight, e.g., from about 1% to about30% by weight of the active compound.

Pharmaceutically Acceptable Carrier

Where desired, the compositions of the invention may include apharmaceutically acceptable vehicle (i.e., carrier). Common carriers andexcipients, such as corn starch or gelatin, lactose, dextrose, sucrose,microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate,sodium chloride, and alginic acid are of interest. Disintegratorscommonly used in the formulations of the invention includecroscarmellose, microcrystalline cellulose, corn starch, sodium starchglycolate and alginic acid.

A liquid composition may comprise a suspension or solution of thecompound or pharmaceutically acceptable salt in a suitable liquidcarrier(s), for example, ethanol, glycerine, sorbitol, non-aqueoussolvent such as polyethylene glycol, oils or water, with a suspendingagent, preservative, surfactant, wetting agent, flavoring or coloringagent. Alternatively, a liquid formulation can be prepared from areconstitutable powder. For example, a powder containing activecompound, suspending agent, sucrose and a sweetener can be reconstitutedwith water to form a suspension; and a syrup can be prepared from apowder containing active ingredient, sucrose and a sweetener.

A composition in the form of a tablet or pill can be prepared using anysuitable pharmaceutical carrier(s) routinely used for preparing solidcompositions. Examples of such carriers include magnesium stearate,starch, lactose, sucrose, microcrystalline cellulose and binders, forexample, polyvinylpyrrolidone. The tablet can also be provided with acolor film coating, or color included as part of the carrier(s). Inaddition, active compound can be formulated in a controlled releasedosage form as a tablet comprising a hydrophilic or hydrophobic matrix.

“Controlled release”, “sustained release”, and similar terms are used todenote a mode of active agent delivery that occurs when the active agentis released from the delivery vehicle at an ascertainable andcontrollable rate over a period of time, rather than dispersedimmediately upon application or injection. Controlled or sustainedrelease may extend for hours, days or months, and may vary as a functionof numerous factors. For the pharmaceutical composition of the presentinvention, the rate of release will depend on the type of the excipientselected and the concentration of the excipient in the composition.Another determinant of the rate of release is the rate of hydrolysis ofthe linkages between and within the units of the polyorthoester. Therate of hydrolysis in turn may be controlled by the composition of thepolyorthoester and the number of hydrolysable bonds in thepolyorthoester. Other factors determining the rate of release of anactive agent from the present pharmaceutical composition includeparticle size, acidity of the medium (either internal or external to thematrix) and physical and chemical properties of the active agent in thematrix.

As such, an active pharmaceutical agent can be placed within anycontrolled-release structure (e.g. a gastroretentive formulation,enteric formulations, timed-release formulations, colonic formulation).Thus the identifier becomes active at the same time that the activeingredient is released. Further, more than one identifier can beincorporated into a controlled release structure, e.g. two identifiers,one of which activates at the start of the controlled release and thesecond in the middle or at the end.

A composition in the form of a capsule can be prepared using routineencapsulation procedures, for example, by incorporation of activecompound and excipients into a hard gelatin capsule. Alternatively, asemi-solid matrix of active compound and high molecular weightpolyethylene glycol can be prepared and filled into a hard gelatincapsule; or a solution of active compound in polyethylene glycol or asuspension in edible oil, for example, liquid paraffin or fractionatedcoconut oil can be prepared and filled into a soft gelatin capsule.

Tablet binders that can be included are acacia, methylcellulose, sodiumcarboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropylmethyl-cellulose, sucrose, starch and ethylcellulose. Lubricants thatcan be used include magnesium stearate or other metallic stearates,stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.

Flavoring agents such as peppermint, oil of wintergreen, cherryflavoring or the like can also be used. Additionally, it may bedesirable to add a coloring agent to make the dosage form moreattractive in appearance or to help identify the product.

Other components suitable for use in the formulations of the presentinvention can be found in Remington's Pharmaceutical Sciences, MacePublishing Company, Philadelphia, Pa., 17th ed. (1985).

Identifier Fabrication

In certain embodiments of interest, the identifier element includes asemiconductor support component. Any of a variety of different protocolsmay be employed in manufacturing the identifier structures andcomponents thereof. For example, molding, deposition and materialremoval, e.g., planar processing techniques, such asMicro-Electro-Mechanical Systems (MEMS) fabrication techniques,including surface micromachining and bulk micromachining techniques, maybe employed. Deposition techniques that may be employed in certainembodiments of fabricating the structures include, but are not limitedto: electroplating, cathodic arc deposition, plasma spray, sputtering,e-beam evaporation, physical vapor deposition, chemical vapordeposition, plasma enhanced chemical vapor deposition, etc. Materialremoval techniques included, but are not limited to: reactive ionetching, anisotropic chemical etching, isotropic chemical etching,planarization, e.g., via chemical mechanical polishing, laser ablation,electronic discharge machining (EDM), etc. Also of interest arelithographic protocols. Of interest in certain embodiments is the use ofplanar processing protocols, in which structures are built up and/orremoved from a surface or surfaces of an initially planar substrateusing a variety of different material removal and deposition protocolsapplied to the substrate in a sequential manner. Illustrativefabrication methods of interest are described in greater detail in PCTapplication serial no. PCT/US2006/16370 titled “Pharma-InformaticsSystem” and filed on Apr. 28, 2006 and published as WO 2006/116718; thedisclosure of which is herein incorporated by reference.

Methods of Making Compositions

A variety of manufacturing protocols may be employed to producecompositions according to the invention. In manufacturing the subjectcompositions, a signal generation element is stably associated with acarrier composition, e.g., pharmaceutical dosage composition, in somemanner. By stably associated is meant that the signal generation elementand the dosage form are not separate from each other, at least untiladministered to the subject in need thereof, e.g., by ingestion. Thesignal generation element may be stably associated with thepharmaceutical carrier/active agent component of the composition in anumber of different ways. In certain embodiments, where thecarrier/active agent component is a solid structure, e.g., such as atablet or pill, the carrier/active agent component is produced in amanner that provides a cavity for the signal generation element. Thesignal generation element is then placed into the cavity and the cavitysealed, e.g., with a biocompatible material, to produce the finalcomposition. For example, in certain embodiments a tablet is producedwith a die that includes a feature which produces a cavity in theresultant compressed tablet. The signal generation element is placedinto the cavity and the cavity sealed to produce the final tablet. In avariation of this embodiment, the tablet is compressed with a removableelement, e.g., in the shape of a rod or other convenient shape. Theremovable element is then removed to produce a cavity in the tablet. Thesignal generation element is placed into the cavity and the cavitysealed to produce the final tablet. In another variation of thisembodiment, a tablet without any cavity is first produced and then acavity is produced in the tablet, e.g., by laser drilling. The signalgeneration element is placed into the cavity and the cavity sealed toproduce the final tablet. In yet other tablet embodiments, an open facepharmaceutical carrier/active agent tablet configuration (e.g., as shownin FIG. 11) is employed, where the active agent/carrier is firstprepared into an annular tablet format that includes a circular opening.For example, in the embodiment shown in FIG. 11, two open annular formatpharmaceutical compositions 111 and 113 are prepared, e.g., by pressing,or other convenient fabrication protocol. Also shown is identifier 115.Following production of the annular tablets 111 and 113, the identifieris positioned in the opening, as shown. The remaining openings 117 and119 are then filled or covered with any of the activating filmsdescribed above (not shown). In yet other embodiments, a tablet isproduced by combining the signal generation element with subparts of thetablet, where the subparts may be pre-made subparts or manufacturedsequentially. For example, in certain embodiments tablets are producedby first making a bottom half of the tablet, placing the signalgeneration element on a location of the bottom half of the tablet, andthen placing top portion of the tablet over the bottom half and signalgeneration element to produce the final desired composition. In certainembodiments, a tablet is produced around a signal generation elementsuch that the signal generation element is located inside of theproduced tablet. For example, a signal generation element, which may ormay not be encapsulated in a biocompatible compliant material, e.g.,gelatin (to protect the signal generation element), is combined withcarrier/active agent precursor, e.g., powder, and compressed or moldedinto a tablet in a manner such that the signal generation element islocated at an internal position of the tablet. Instead of molding orcompressing, the carrier/active agent component is, in certainembodiments, sprayed onto the signal generation element in a manner thatbuilds up the tablet structure. In yet another embodiment, the activeagent/carrier component precursor may be a liquid formulation which iscombined with the signal generation element and then solidified toproduce the final composition. In yet other embodiments, pre-madetablets may be fitted with the signal generation element by stablyattaching the signal generation element to the tablet. Of interest areprotocols that do not alter the properties of the tablet, e.g.,dissolution etc. For example, a gelatin element that snap fits onto oneend of a tablet and has the chip integrated with it is employed incertain embodiments. The gelatin element is colored in certainembodiments to readily identify tablets that have been fitted with thesignal generation element. Where the composition has an activeagent/carrier composition filled capsule configuration, e.g., such as agelatin capsule filled configuration, the signal generation element maybe integrated with a capsule component, e.g., top or bottom capsule, andthe capsule filled with the active agent/carrier composition to producethe final composition. The above reviewed methods of manufacture aremerely illustrative of the variety of different ways in which thecompositions of the invention may be manufactured.

Systems

Also provided are systems that include the subject compositions. Systemsof the subject invention include, in certain embodiments, one or morecontrolled activation identifiers, e.g., as reviewed above, as well as asignal detection component, e.g., in the form of a receiver. The signaldetection component may vary significantly depending on the nature ofthe signal that is generated by the signal generation element of thecomposition, e.g., as reviewed above.

In certain embodiments, the signal detection component is an implantablecomponent. By implantable component is meant that the signal detectioncomponent is designed, i.e., configured, for implantation into asubject, e.g., on a semi-permanent or permanent basis. In theseembodiments, the signal detection component is in vivo during use. Inyet other embodiments, the signal detection component is ex vivo, bywhich is meant that the detection component is present outside of thebody during use. In certain of these embodiments, as developed ingreater detail below, either separate from or integrated with the exvivo detection component may be a dosage dispenser element, e.g., fordispensing dosages of the compositions based on signal detected from thesignal generation element of the detector. Such features may also bepresent in implantable detection components, e.g., to provide a closedloop administration system that administers a subsequent dosage based oninput about ingestion of a previous dosage.

As reviewed above, in certain embodiments the signal generation elementof the composition is activated upon contact with a target body site. Incertain of these embodiments, the signal detection component isactivated upon detection of a signal from the signal generation element.In certain of these embodiments, the composition generates anintermittent signal. In certain of these embodiments, the detectionelement is capable of simultaneously detecting multiple compositions.

Signal receivers for use in the invention are further described in PCTapplication serial no. PCT/US2006/16370 titled “Pharma-InformaticsSystem” and filed on Apr. 28, 2006 and published as WO 2006/116718, aswell as provisional application Ser. Nos. 60/887,780 titled “SignalReceivers for Pharma-Informatics Systems,” and filed on Feb. 1, 2007;60/949,223 titled “Ingestible Even Marker,” and filed on Jul. 11, 2007and 60/956,694 titled “Personal Health Signal Receivers,” and filed onAug. 18, 2007; the disclosures of which are herein incorporated byreference.

In certain embodiments, the signal detection component includes acardiac monitoring element, such as shown in the system of FIG. 10. FIG.10 provides a diagrammatic, exemplary representation of a pill/capsuleembodiment of the present invention, in which the composition isconfigured as an orally ingestible pharmaceutical formulation in theform of a pill or capsule. The stomach 12 of the patient 10 who ingeststhe composition 14 is shown. This “smart pill” is shown as it hastraveled from the mouth 16 to inside 18 the patients stomach. Uponreaching the stomach, the pill/capsule undergoes a dissolving processwith both the mechanical action of the stomach and the various chemicalmaterials in the stomach fluids, such as hydrochloric acid and otherdigestive agents. FIG. 10 also shows an implanted cardiovascular device“can” 8 and a lead 6, which components are employed to monitor anddetect the signal emitted from pill 14. The monitoring device can bepositioned in other locations as well, such as subcutaneously, in theheart, or in the waist near the stomach, for example. Positioning may besuggested by a particular application.

Methods

Controlled activation identifiers of the invention find use in a varietyof different applications, including delivery of pharmaceutical agents,in diagnostic and monitoring applications, etc. In methods where theidentifiers are employed in compositions that include one or morepharmaceutically active agents, an effective amount of a composition ofthe invention is administered to a subject in need of the active agentpresent in the composition, where “effective amount” means a dosagesufficient to produce the desired result, e.g., an improvement in adisease condition or the symptoms associated therewith, theaccomplishment of a desired physiological change, etc. The amount thatis administered may also be viewed as a therapeutically effectiveamount. A “therapeutically effective amount” means the amount that, whenadministered to a subject for treating a disease, is sufficient toeffect treatment for that disease.

The composition may be administered to the subject using any convenientmeans capable of producing the desired result, where the administrationroute depends, at least in part, on the particular format of thecomposition, e.g., as reviewed above. As reviewed above, thecompositions can be formatted into a variety of formulations fortherapeutic administration, including but not limited to solid, semisolid or liquid, such as tablets, capsules, powders, granules,ointments, solutions, suppositories and injections. As such,administration of the compositions can be achieved in various ways,including, but not limited to: oral, buccal, rectal, parenteral,intraperitoneal, intradermal, transdermal, intracheal, etc.,administration. In pharmaceutical dosage forms, a given composition maybe administered alone or in combination with other pharmaceuticallyactive compounds, e.g., which may also be compositions having signalgeneration elements stably associated therewith.

The subject methods find use in the treatment of a variety of differentconditions, including disease conditions. The specific diseaseconditions treatable by with the subject compositions are as varied asthe types of active agents that can be present in the subjectcompositions. Thus, disease conditions include, but are not limited to:cardiovascular diseases, cellular proliferative diseases, such asneoplastic diseases, autoimmune diseases, hormonal abnormality diseases,infectious diseases, pain management, and the like.

By treatment is meant at least an amelioration of the symptomsassociated with the disease condition afflicting the subject, whereamelioration is used in a broad sense to refer to at least a reductionin the magnitude of a parameter, e.g. symptom, associated with thepathological condition being treated. As such, treatment also includessituations where the pathological condition, or at least symptomsassociated therewith, are completely inhibited, e.g. prevented fromhappening, or stopped, e.g. terminated, such that the subject no longersuffers from the pathological condition, or at least the symptoms thatcharacterize the pathological condition. Accordingly, “treating” or“treatment” of a disease includes preventing the disease from occurringin an animal that may be predisposed to the disease but does not yetexperience or exhibit symptoms of the disease (prophylactic treatment),inhibiting the disease (slowing or arresting its development), providingrelief from the symptoms or side-effects of the disease (includingpalliative treatment), and relieving the disease (causing regression ofthe disease). For the purposes of this invention, a “disease” includespain.

A variety of subjects are treatable according to the present methods.Generally such subjects are “mammals” or “mammalian,” where these termsare used broadly to describe organisms which are within the classmammalia, including the orders carnivore (e.g., dogs and cats), rodentia(e.g., mice, guinea pigs, and rats), and primates (e.g., humans,chimpanzees, and monkeys). In representative embodiments, the subjectswill be humans.

In certain embodiments, the subject methods, as described above, aremethods of managing a disease condition, e.g., over an extended periodof time, such as 1 week or longer, 1 month or longer, 6 months orlonger, 1 year or longer, 2 years or longer, 5 years or longer, etc. Thesubject methods may be employed in conjunction with one or moreadditional disease management protocols, e.g., electrostimulation basedprotocols in cardiovascular disease management, such as pacingprotocols, cardiac resynchronization protocols, etc; lifestyle, such adiet and/or exercise regimens for a variety of different diseaseconditions; etc.

In certain embodiments, the methods include modulating a therapeuticregimen based data obtained from the compositions. For example, data maybe obtained which includes information about patient compliance with aprescribed therapeutic regimen. This data, with or without additionalphysiological data, e.g., obtained using one or more sensors, such asthe sensor devices described above, may be employed, e.g., withappropriate decision tools as desired, to make determinations of whethera given treatment regimen should be maintained or modified in some way,e.g., by modification of a medication regimen and/or implant activityregimen. As such, methods of invention include methods in which atherapeutic regimen is modified based on signals obtained from thecomposition(s).

In certain embodiments, also provided are methods of determining thehistory of a composition of the invention, where the compositionincludes an active agent, an identifier element and a pharmaceuticallyacceptable carrier. In certain embodiments where the identifier emits asignal in response to an interrogation, the identifier is interrogate,e.g., by a wand or other suitable interrogation device, to obtain asignal. The obtained signal is then employed to determine historicalinformation about the composition, e.g., source, chain of custody, etc.

In yet other embodiments where the identifier is one that survivesdigestion, the methods generally include obtaining the signal generationelement of the composition, e.g., by retrieving it from a subject thathas ingested the composition, and then determining the history of thecomposition from obtained signal generation element. For example, wherethe signal generation element includes an engraved identifier, e.g.,barcode or other type of identifier, the engraved identifier may beretrieved from a subject that has ingested the composition and then readto identify at least some aspect of the history of the composition, suchas last known purchaser, additional purchasers in the chain of custodyof the composition, manufacturer, handling history, etc. In certainembodiments, this determining step may include accessing a database oranalogous compilation of stored history for the composition.

The present invention provides the clinician an important new tool intheir therapeutic armamentarium: automatic detection and identificationof pharmaceutical agents actually delivered into the body. Theapplications of this new information device and system are multi-fold.Applications include, but are not limited to: (1) monitoring patientcompliance with prescribed therapeutic regimens; (2) tailoringtherapeutic regimens based on patient compliance: (3) monitoring patientcompliance in clinical trials; (4) monitoring usage of controlledsubstances; and the like. Each of these different illustrativeapplications is reviewed in greater detail below in PCT/US2006/16370titled “Pharma-Informatics System” and filed on Apr. 28, 2006 andpublished as WO 2006/116718; the disclosure of which is hereinincorporated by reference.

Also of interest are methods in which the identifier is ingested apartfrom any pharmaceutical agent. Such methods include those in which theidentifier is employed as an ingestible event marker. In such methods,the identifier is ingested without a pharmaceutically active agent. Theidentifier may be ingested in a pharmaceutically acceptable vehicle,e.g., as described above. Specific applications in which the identifieris employed as an ingestible event marker include, but are not limitedto, those described in U.S. Provisional Application Ser. No. 60/949,223titled “Ingestible Event Marker,” and filed on Jul. 11, 2007; thedisclosures of which are herein incorporated by reference.

One example of a specific application in which the controlled activationidentifier is not administered with an active agent and is insteademployed as an ingestible event marker is the application of monitoringGI tract motility. In such applications, a controlled activation devicethat activates only at high pH is employed to determine the transit timefrom ingestion to the small intestine. In a variation of thisembodiment, multiple devices that activate in different parts of the GItract are employed, where this embodiment may be used for mapping theresidence time of the device in various parts of the GI tract. Forexample, in one instance three controlled activation identifiers (whichmay be present in the same pill or separate pills) are employed. Thefirst identifier is configured to activate immediately upon ingestion(e.g., which it reaches the stomach). The second controlled activationidentifier includes a low pH-insoluble, high-pH soluble coating (e.g.,Eudragit) that delays activation until the identifier reaches the smallintestine. The third identifier includes a controlled activation elementa coating (e.g., amylase+ethyl cellulose) that is only soluble in thecolon. From the activation time of the various identifiers one candetermine or measure the transition time to the stomach, smallintestine, and colon, and thereby gain a detailed data collection of thesubject's gastrointestinal motility.

Kits

Also provided are kits for practicing the subject methods. Kits mayinclude one or more compositions of the invention, as described above.The dosage amount of the one or more pharmacological agents provided ina kit may be sufficient for a single application or for multipleapplications. Accordingly, in certain embodiments of the subject kits asingle dosage amount of a pharmacological agent is present and incertain other embodiments multiple dosage amounts of a pharmacologicalagent may be present in a kit. In those embodiments having multipledosage amounts of pharmacological agent, such may be packaged in asingle container, e.g., a single tube, bottle, vial, and the like, orone or more dosage amounts may be individually packaged such thatcertain kits may have more than one container of a pharmacologicalagent. Suitable means for delivering one or more pharmacological agentsto a subject may also be provided in a subject kit. In certainembodiments the kits may also include a signal receiving element, asreviewed above. In certain embodiments, the kits may also include anexternal monitor device, e.g., as described above, which may provide forcommunication with a remote location, e.g., a doctor's office, a centralfacility etc., which obtains and processes data obtained about the usageof the composition.

The subject kits may also include instructions for how to practice thesubject methods using the components of the kit. The instructions may berecorded on a suitable recording medium or substrate. For example, theinstructions may be printed on a substrate, such as paper or plastic,etc. As such, the instructions may be present in the kits as a packageinsert, in the labeling of the container of the kit or componentsthereof (i.e., associated with the packaging or sub-packaging) etc. Inother embodiments, the instructions are present as an electronic storagedata file present on a suitable computer readable storage medium, e.g.CD-ROM, diskette, etc. In yet other embodiments, the actual instructionsare not present in the kit, but means for obtaining the instructionsfrom a remote source, e.g. via the internet, are provided. An example ofthis embodiment is a kit that includes a web address where theinstructions can be viewed and/or from which the instructions can bedownloaded. As with the instructions, this means for obtaining theinstructions is recorded on a suitable substrate.

Some or all components of the subject kits may be packaged in suitablepackaging to maintain sterility. In many embodiments of the subjectkits, the components of the kit are packaged in a kit containmentelement to make a single, easily handled unit, where the kit containmentelement, e.g., box or analogous structure, may or may not be an airtightcontainer, e.g., to further preserve the sterility of some or all of thecomponents of the kit.

It is to be understood that this invention is not limited to particularembodiments described, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

1.-51. (canceled)
 52. An apparatus for use with a pharmaceuticallyacceptable carrier, the apparatus comprising: a first electrode; asecond electrode; wherein the first electrode and the second electrodecomprise dissimilar materials configured to generate an electricalpotential upon contracting an ionic solution; a circuit electricallycoupled to each of the first electrode and the second electrode, thecircuit configured to generate a signal; wherein the circuit is stablyfittable to the pharmaceutically acceptable carrier; and a protectivelayer enclosing at least one of the first electrode and the secondelectrode from the ionic solution, the protective layer configured to bedissolved by the ionic solution.
 53. The apparatus of claim 52, whereinthe protective layer encloses both the first electrode and the secondelectrode.
 54. The apparatus of claim 52, wherein the signal comprisesan RF signal.
 55. The apparatus of claim 52, wherein the circuit furthercomprises a coil, the circuit configured to generate an oscillatingcurrent when powered by the first electrode and the second electrode andthe coil configured to generate an RF signal according to theoscillating current.
 56. The apparatus of claim 52, wherein theprotective layer comprises a time-controlled dissolution composition.57. The apparatus of claim 52, wherein the protective layer comprises acomposition configured to dissolve upon contacting a solution embodyinga target level of a property, the property selected from the groupconsisting of pH and conductivity.